Radioisotopes are widely used in the fields of life science, research and medicine, for example, in nuclear medicine, diagnosis, radiotherapy, biochemical analysis, as well as diagnostic and therapeutic pharmaceuticals.
One such important application for radioisotopes is the diagnosis and therapy of diseases, such as cancer. For example, there has been considerable progress during the last two decades in the use of radio-labelled tumor-selective monoclonal antibodies in the diagnosis and therapy of cancer. The concept of localizing the cytotoxic radionuclide to the cancer cell is an important supplement to conventional forms of radiotherapy. In theory the intimate contract between a radioactive antibody conjugate and a target cell enables the absorbed radiation dose to be concentrated at the site of abnormality with minimal injury to the normal surrounding cells and tissues [Bruland O S. Cancer therapy with radiolabelled antibodies. An overview. Acta Oncol. 1995; 34(8):1085-94].
Furthermore, the use of monoclonal antibodies to deliver radioisotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native antibodies. Since the alpha- and beta-particles emitted during the decay of radioisotopes differ in significant ways, proper selection of isotope and antibody combinations is crucial to making radioimmunotherapy a standard therapeutic modality. Because of the short path length (50-80 microm) and high linear energy transfer (approximately 100 keV/microm) of alpha-emitting radioisotopes, targeted alpha-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissues than beta-emitters. These properties make targeted alpha-particle therapy ideal for the elimination of minimal residual or micrometastatic disease. Radioimmunotherapy using alpha-emitters such as (213)Bi, (211)At, and (225)Ac has shown activity in several in vitro and in vivo experimental models as well as in clinical trials. Further advances will require investigation of more potent isotopes, new sources and methods of isotope production, improved chelation techniques, better methods for pharmacokinetic and dosimetric modeling, and new methods of isotope delivery such as pretargeting. [Mulford D A, Scheinberg D A, Jurcic J G. The promise of targeted alpha-particle therapy. J Nucl Med. 2005 January; 46 Suppl 1:199 S-204S.]
In addition, radioimmunotherapy (RIT) combines the advantages of targeted radiation therapy and specific immunotherapy using monoclonal antibodies. RIT can be used either to target tumor cells or to specifically suppress immunocompetent host cells in the setting of allogeneic transplantation. The choice of radionuclide used for RIT depends on its distinct radiation characteristics and the type of malignancy or cells targeted. In general, beta-emitters with their lower energy and longer path length are more suitable to target bulky, solid tumors whereas alpha-emitters with their high linear energy transfer and short path length are better suited to target hematopoietic cells (normal or malignant). Different approaches of RIT such as the use of stable radioimmunoconjugates or of pretargeting strategies are available. [Bethge W A, Sandmaier B M. Targeted cancer therapy using radiolabeled monoclonal antibodies. Technol Cancer Res Treat. 2005 August; 4(4):393-405.
Also the method SIRT (selective internal radiation therapy) or radioembolization has been developed which is similar to chemoembolization but uses radioactive microspheres (microscopic particles or beads). Thereby, radioisotopes are incorporated directly into the microspheres in order to deliver radiation directly to its destination, e.g. the tumor. The loaded spheres/beads are e.g. injected through a catheter into the blood vessel supplying the tumor. The spheres/beads become lodged within the tumor vessels where they deliver local radiation that causes tumor death. This technique allows for a higher dose of radiation to be used to kill the tumor without subjecting adjacent healthy tissue to harmful levels of radiation. Radioembolization has been described utilizing, for example, 90Y (Herba M J, Thirlwell M P. Radioembolization for hepatic metastases. Semin Oncol. 2002 April; 29(2):152-9.) or 188Re (Wunderlich G, Pinkert J, Stintz M, Kotzerke J. Labeling and biodistribution of different particle materials for radioembolization therapy with 188Re. Appl Radiat Isot. 2005 May; 62(5):745-50.)
However, the presently used methods in radioisotope production have reached their limits and there is a strong need for improved methods. This applies in particular to the isotopic purity, the specific activity and the range of available radionuclides.
With the growing complexity of positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging and the developments in systemic radionuclide therapy there is a growing need for radioisotope preparations with higher radiochemical and radionuclic purity that has not been achievable before. Especially important for the new applications is the specific activity of the radiotracer.
Furthermore, an implementation of the break-through in development of the drug target delivery systems of new methods of cancer therapy is limited due to the lack of availability of the existing radionuclides with optimal decay characteristics for such an application.